PROJECT SUMMARY/ABSTRACT Impaired memory is an important component of diseases such as Alzheimer's disease, temporal lobe epilepsy, depression, and schizophrenia that collectively affect over twenty million Americans. Our long-range goal is to contribute to a better understanding of the neural mechanisms that underlie memory processes, in order to bring us closer to developing new therapies for these disabled patients. While it has long been recognized that medial temporal lobe structures are important for mnemonic processing, studies in rodents have also identified exquisite spatial representations in these regions in the form of place cells in the hippocampus and grid and border cells in the entorhinal cortex. A recent area of investigation has focused on understanding the generation of these spatial representations, for which theta-band activity has been hypothesized to play a major role. However, very little is known about whether neurons in the primate hippocampal formation demonstrate theta-band rhythmic activity and almost nothing is known about potentially analogous spatial representations in the primate hippocampus and entorhinal cortex. The lack of understanding in this area inhibits our ability to link the large body of previous findings from rodents to humans and prevents a full understanding of the function of these structures. Based on preliminary data, we hypothesize that neural activity in the primate hippocampus and entorhinal cortex reflects an allocentric spatial coordinate frame, during both 2-D visuospatial exploration and 3-D virtual navigation. The experiments proposed here will directly test this hypothesis, using multi-electrode recordings of spiking activity and the local field potential (LFP) in the hippocampus and entorhinal cortex of rhesus monkeys engaged in free-viewing memory tasks and virtual navigation. We will examine modulations in single-unit firing rates, LFP power, and spike-field neuronal synchronization with respect to eye fixation location, saccade direction, heading direction, location in virtual space, and memory performance. Recordings will be carried out throughout these structures in order to identify the anatomical distribution of particular representations. The proposed experiments have the following potential outcomes: 1) to demonstrate whether the structure of the spatial code in the primate hippocampal formation is universal across stimulus domains, i.e., virtual 3-D and visual space, 2) to inform models that describe the generation of these spatial responses by identifying the extent to which these representations are related to network oscillatory activity, and 3) to identify the extent to which neural activity in the hippocampal formation is modulated by visuospatial and environmental exploration and how this modulation impacts memory formation.